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PHRM 864: Therapeutics IV > Alkylating Agents & Platinum Agents > Flashcards

Alkylating Agents & Platinum Agents Flashcards

1
Q

In what way do Alkyating Agents work?

A
  • Creating electrophilic intermediates that react with nucleophiles on DNA
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2
Q

Within DNA, what is the most common site of Alkylation?

A
  • Guanine N7
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3
Q

When it says that the most effective cancer drugs are “bifunctional”, what does that mean?

A
  • There are two groups that get alkylated = inter or intra strands
  • Also creates crosslinks
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4
Q

Why was mustard gas first used within medicine?

A
  • Used as chemical warfare in WWI
  • Doctors saw decrease in Lymph Nodes and Myleosuppression
  • used in treatment for leukemia and lymphoma
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5
Q

What is the mechanism of action for the Nitrogen Mustard?

A
  • Creates an aziridinium ion that is electrophilic, making it want to bind with the nucleophilic Guanine N7
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6
Q

What are the effects caused by the alkylation?

A
  • It causes the inter [separate] and intra [same] strands that inhibit DNA replication
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7
Q

For Alkylating Agents, what phase of the cell cycle do they mainly affect?

A
  • Non Cell cycles specific as they just damage all DNA agents
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8
Q

What are some of the side effects caused by the alkylating agents?.

A
  • Nausea, Vomiting, Myleosuppression, Gut Mucosa = caused by the rapid DNA proliferation
  • Monoadduct
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9
Q

What does it mean when the alkylating agents are monoadduct?

A
  • Mutagenic, carinogenic, teratogenic
  • Has the ability to develop a second tumor
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10
Q

What is Mechlorethamine?

A
  • 1st Alkylating Agent that is VERY reactive
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11
Q

What are the side effects for ALL alkylating agents?

A
  • Myleosuppression
  • Nausea & Vomiting
  • Carcinogenic & Teratogenic
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12
Q

Since Mechlorethemine is so reactive, what are TWO strategies that are used to reduce the reactivity

A
  • Decrease nucleophiicity of Nitrogen by adding aryl groups
  • Prodrug Strategy
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13
Q

How does adding the aryl group help with reducing reactivity?

A
  • Adding an aryl group will make the pKa of the group to drop = decrease in nucleophile
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14
Q

What drugs within alkylating helps with creating those aryl groups decreaings the nucleophilicity?

A
  • Chlorambucial
  • Also Bendamustine & Melphalan
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15
Q

What is the drug that helps with the Prodrug Strategy within alkylating groups?

A
  • Cyclophosphamide
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16
Q

What is the mechanism of action for Cyclophosphamide?

A
  • Need P450 to hydroxlyate it creating the electrophilic compound and acrolein
17
Q

What must Cyclophosphamide be converted to to actaully work?

A
  • Phosphormaide Mustard
  • Aldehyde Dehydrogenase is inactivated
18
Q

What are some of the side effects for Cyclophosphamide?

A
  • Mild Myelosuppression = ADH in bone
  • Hemorrhagic Cyctitis
19
Q

What causes the Hemorrhagic Cyctitis caused by using Cyclophosphamide?

A
  • Acrolein = By Product
  • Toxic toward the bladder since it accumulates in the urine
20
Q

What is one way that we can treat/prevent hemorrhagic cystits from forming?

A
  • Ussing Mesna = Contains charged sulfonate groups so it does not penetrate cells [accumulates in urine] binds to acrolein to inactivate it
21
Q

What is the way that Platinum Drugs are used?

A
  • Very similar as alkylating agents as they make crosslinks BUT they are NOT alkylating agents
22
Q

What is the mechanism of action for the platinum drugs?

A
  • Platinum complex where H20 will bind to the leaving groups creating an AQUO FORM.
  • Aquo Form will then create those crosslinks with DNA
23
Q

In what way does the Aquo Forms react with DNA?

A
  • Intrastanded Crosslinks with Guanine N7 & Adenine N7
24
Q

What is the main Platinum drug that is used in the class?

A
  • Cisplatin
25
Q

What is important to know about Cisplatin?

A
  • Produces primarly Intrastrand Crosslinks from nonenzymatic conversion
  • More sensitve in G1 than in S phase
26
Q

What are some of the side effects of Cisplatin?

A
  • Dose-Limiting Nephrotoxicitity
  • Severe Nausea & Vomting
  • Minimal Bone Marrow toxicit
  • Peripheral Neuropathy
  • Hearing loss
27
Q

What are some drug resistance mechanisms for the platinum drugs?

A
  • Increase in conc. of glutathione [VERY HIGH reactivity toward electrophilic]
  • Increased expression of Glutathione S-Transferase [what catalyses it]

PHRM 864: Therapeutics IV (28 decks)

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